Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hepatocellular carcinoma

Abstract

Liver cancer is the second leading cause of cancer-related deaths globally and has an incidence of approximately 850,000 new cases per year. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer. The main risk factors for developing HCC are well known and include hepatitis B and C virus infection, alcohol intake and ingestion of the fungal metabolite aflatoxin B1. Additional risk factors such as non-alcoholic steatohepatitis are also emerging. Advances in the understanding of the molecular pathogenesis of HCC have led to identification of critical driver mutations; however, the most prevalent of these are not yet druggable targets. The molecular classification of HCC is not established, and the Barcelona Clinic Liver Cancer staging classification is the main clinical algorithm for the stratification of patients according to prognosis and treatment allocation. Surveillance programmes enable the detection of early-stage tumours that are amenable to curative therapies — resection, liver transplantation or local ablation. At more developed stages, only chemoembolization (for intermediate HCC) and sorafenib (for advanced HCC) have shown survival benefits. There are major unmet needs in HCC management that might be addressed through the discovery of new therapies and their combinations for use in the adjuvant setting and for intermediate- and advanced-stage disease. Moreover, biomarkers for therapy stratification, patient-tailored strategies targeting driver mutations and/or activating signalling cascades, and validated measurements of quality of life are needed. Recent failures in the testing of systemic drugs for intermediate and advanced stages have indicated a need to refine trial designs and to define novel approaches.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The global burden of HCC.
Figure 2: Liver cancer incidence according to region and sex.
Figure 3: Cancer progression and driver genes.
Figure 4: BCLC staging system and therapeutic strategy.
Figure 5: Molecular targeted therapies for HCC and their target signalling pathways.

References

  1. 1

    Torre, L. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

    Article  PubMed  Google Scholar 

  2. 2

    GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385, 117–171 (2014).

    PubMed Central  Google Scholar 

  3. 3

    European Association For The Study Of The Liver & European Organisation For Research And Treatment Of Cancer. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56, 908–943 (2012). This article outlines the European consensus guidelines for the management of HCC, including the definition of treatment allocation criteria according to evidence.

    Article  Google Scholar 

  4. 4

    Liu, J. & Fan, D. Hepatitis B in China. Lancet 369, 1582–1583 (2007).

    Article  PubMed  Google Scholar 

  5. 5

    Mohd Hanafiah, K., Groeger, J., Flaxman, A. D. & Wiersma, S. T. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 57, 1333–1342 (2013).

    Article  PubMed  Google Scholar 

  6. 6

    Mohamoud, Y. A., Mumtaz, G. R., Riome, S., Miller, D. & Abu-Raddad, L. J. The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect. Dis. 13, 288 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    National Center for Health Statistics. Health, United States, 2014: With Special Feature on Adults Aged 55–64 (National Center for Health Statistics, 2015).

  9. 9

    Omer, R. E. et al. Population-attributable risk of dietary aflatoxins and hepatitis B virus infection with respect to hepatocellular carcinoma. Nutr. Cancer 48, 15–21 (2004).

    Article  PubMed  Google Scholar 

  10. 10

    Laursen, L. A preventable cancer. Nature 516, S2–S3 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Sartorius, K., Sartorius, B., Aldous, C., Govender, P. S. & Madiba, T. E. Global and country underestimation of hepatocellular carcinoma (HCC) in 2012 and its implications. Cancer Epidemiol. 39, 284–290 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Nault, J.-C. et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 10, 1187–1193 (2015).

    Article  CAS  Google Scholar 

  14. 14

    Zucman-Rossi, J., Villanueva, A., Nault, J.-C. & Llovet, J. M. The genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 5, 1226–1239 (2015).

    Article  CAS  Google Scholar 

  15. 15

    Bruix, J. & Sherman, M. Management of hepatocellular carcinoma: an update. Hepatology 53, 1020–1022 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Forner, A., Llovet, J. M. & Bruix, J. Hepatocellular carcinoma. Lancet 379, 1245–1255 (2012).

    Article  Google Scholar 

  17. 17

    Llovet, J. M. et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359, 1734–1739 (2002). This paper reports a positive RCT supporting the use of TACE in intermediate-stage HCC.

    Article  PubMed  Google Scholar 

  18. 18

    Llovet, J. M. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37, 429–442 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008). This paper details a positive RCT supporting the use of sorafenib in advanced-stage HCC. It was the first RCT to demonstrate survival benefits for a systemic drug in HCC and provided the rationale for approval of this drug in the management of HCC.

    Article  CAS  Google Scholar 

  20. 20

    Yang, J. D. et al. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 9, 64–70 (2011).

    Article  PubMed  Google Scholar 

  21. 21

    Lok, A. S. et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 136, 138–148 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Hsu, I. C. et al. Mutational hotspot in the P53 gene in human hepatocellular carcinomas. Nature 350, 427–428 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Bruix, J. & Sherman, M. Management of hepatocellular carcinoma. Hepatology 42, 1208–1236 (2005).

    Article  PubMed  Google Scholar 

  24. 24

    Yang, D. et al. Impact of sex on the survival of patients with hepatocellular carcinoma: a surveillance, epidemiology, and end results analysis. Cancer 120, 3707–3716 (2014).

    Article  PubMed  Google Scholar 

  25. 25

    Mittal, S. et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin. Gastroenterol. Hepatol. 13, 594–601.e1 (2015).

    Article  PubMed  Google Scholar 

  26. 26

    Chang, M. H. et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J. Natl Cancer Inst. 101, 1348–1355 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Wong, G. L. et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology 58, 1537–1547 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Singal, A. G., Volk, M. L., Jensen, D., Di Bisceglie, A. M. & Schoenfeld, P. S. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin. Gastroenterol. Hepatol. 8, 280–288.e1 (2010).

    Article  PubMed  Google Scholar 

  29. 29

    Singh, S., Singh, P. P., Singh, A. G., Murad, M. H. & Sanchez, W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144, 323–332 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Marquardt, J. U., Andersen, J. B. & Thorgeirsson, S. S. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat. Rev. Cancer 15, 653–667 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Alizadeh, A. A. et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Guichard, C. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44, 694–698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 44, 505–511 (2015). This paper reports the largest whole-exome sequencing study in a cohort of HCC patients from western countries (Europe and North America).

    Article  CAS  Google Scholar 

  34. 34

    Nault, J. C. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 4, 2218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Ahn, S.-M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 60, 1972–1982 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Nault, J. C. et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 60, 1983–1992 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Pilati, C. et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 25, 428–441 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Totoki, Y. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46, 1267–1273 (2014). This paper reports the largest whole-exome sequencing study in a cohort of HCC patients from Asia.

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Di Tommaso, L. et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 45, 725–734 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Di Tommaso, L. et al. The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J. Hepatol. 50, 746–754 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Llovet, J. M. et al. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 131, 1758–1767 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Wurmbach, E. et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45, 938–947 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Paradis, V. et al. Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale real-time RT-PCR approach: determination of a molecular diagnostic index. Am. J. Pathol. 163, 733–741 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Günes, C. & Rudolph, K. L. The role of telomeres in stem cells and cancer. Cell 152, 390–393 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Satyanarayana, A. et al. Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol. Cell. Biol. 24, 5459–5474 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Farazi, P. A. et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 63, 5021–5027 (2003).

    CAS  PubMed  Google Scholar 

  47. 47

    Hartmann, D. et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 53, 1608–1617 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Calado, R. T. et al. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 53, 1600–1607 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N. & DePinho, R. A. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 287, 1253–1258 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Lechel, A. et al. Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 132, 1465–1475 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Kotoula, V. et al. Expression of human telomerase reverse transcriptase in regenerative and precancerous lesions of cirrhotic livers. Liver 22, 57–69 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Bartosch, B., Thimme, R., Blum, H. E. & Zoulim, F. Hepatitis C virus-induced hepatocarcinogenesis. J. Hepatol. 51, 810–820 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Neuveut, C., Wei, Y. & Buendia, M. A. Mechanisms of HBV-related hepatocarcinogenesis. J. Hepatol. 52, 594–604 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Wang, J., Chenivesse, X., Henglein, B. & Bréchot, C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343, 555–557 (1990).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Sung, W.-K. et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 44, 765–769 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    De La Coste, A. et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl Acad. Sci. USA 95, 8847–8851 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Audard, V. et al. Cholestasis is a marker for hepatocellular carcinomas displaying β-catenin mutations. J. Pathol. 212, 345–352 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Bressac, B., Kew, M., Wands, J. & Ozturk, M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431 (1991).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Amaddeo, G. et al. Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas. Gut 64, 820–829 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Fei, Q. et al. Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53. Nat. Commun. 6, 8651 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Wong, C.-M. et al. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. Hepatology 63, 474–487 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Villanueva, A. et al. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology 61, 1945–1956 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Herceg, Z. & Paliwal, A. Epigenetic mechanisms in hepatocellular carcinoma: how environmental factors influence the epigenome. Mutat. Res. 727, 55–61 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Sporn, M. B. & Liby, K. T. NRF2 and cancer: the good, the bad and the importance of context. Nat. Rev. Cancer 12, 564–571 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68, 6779–6788 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Sawey, E. T. et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 19, 347–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Horwitz, E. et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 4, 730–743 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Rudalska, R. et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20, 1138–1146 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Weber, J. et al. CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice. Proc. Natl Acad. Sci. USA 112, 13982–13987 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Hoshida, Y. et al. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin. Liver Dis. 30, 35–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Lee, J.-S. et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 40, 667–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Lee, J.-S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med. 12, 410–416 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Hoshida, Y. et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 69, 7385–7392 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Lachenmayer, A. et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin. Cancer Res. 18, 4997–5007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Hernandez-Gea, V., Toffanin, S., Friedman, S. L. & Llovet, J. M. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144, 512–527 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Wada, Y., Nakashima, O., Kutami, R., Yamamoto, O. & Kojiro, M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27, 407–414 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Hoshida, Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359, 1995–2004 (2008). This manuscript is the first to define the importance of the ‘cancer field effect’ in the prognosis of patients with HCC after resection.

  82. 82

    Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Thomson, A. W. & Knolle, P. A. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

    Article  CAS  Google Scholar 

  86. 86

    Bauer, J. et al. Lymphotoxin, NF-κB, and cancer: the dark side of cytokines. Dig. Dis. 30, 453–468 (2012).

    Article  PubMed  Google Scholar 

  87. 87

    Taniguchi, K. & Karin, M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin. Immunol. 26, 54–74 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Hussain, S. P., Hofseth, L. J. & Harris, C. C. Radical causes of cancer. Nat. Rev. Cancer 3, 276–285 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Kiraly, O., Gong, G., Olipitz, W., Muthupalani, S. & Engelward, B. P. Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo. PLoS Genet. 11, e1004901 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Zhang, D. Y. et al. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Guthttp://dx.doi.org/10.1136/gutjnl-2015-309655 (2015).

  92. 92

    Campbell, J. S. et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc. Natl Acad. Sci. USA 102, 3389–3394 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Dapito, D. H. & Schwabe, R. F. Hepatic Stellate Cells and Liver Cancer. Stellate Cells in Health and Disease (Elsevier, 2015).

    Google Scholar 

  94. 94

    Lee, Y. A., Wallace, M. C. & Friedman, S. L. Pathobiology of liver fibrosis: a translational success story. Gut 64, 830–841 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Chang, M. H. et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N. Engl. J. Med. 336, 1855–1859 (1997). A study demonstrating the effect of universal HBV vaccination in decreasing the incidence of HCC in Taiwan.

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Yuen, M.-F. et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J. Hepatol. 50, 80–88 (2009).

    Article  PubMed  Google Scholar 

  97. 97

    Wong, V. W.-S. et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J. Clin. Oncol. 28, 1660–1665 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Wong, G. L.-H. et al. Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B. J. Hepatol. 60, 339–345 (2014).

    Article  PubMed  Google Scholar 

  99. 99

    Chen, C.-J. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295, 65–73 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Yang, H.-I. et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J. Clin. Oncol. 28, 2437–2444 (2010).

    Article  PubMed  Google Scholar 

  101. 101

    Yang, H.-I. et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol. 12, 568–574 (2011).

    Article  PubMed  Google Scholar 

  102. 102

    Lee, M.-H. et al. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology 58, 546–554 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Wong, G. L.-H. et al. Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment. Gastroenterology 144, 933–944 (2013).

    Article  PubMed  Google Scholar 

  104. 104

    Arends, P. et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut 64, 1289–1295 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Liaw, Y.-F. et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med. 351, 1521–1531 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Papatheodoridis, G. V. et al. Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. J. Hepatol. 62, 363–370 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Ogawa, E. et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study. J. Hepatol. 58, 495–501 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Harada, N. et al. Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin. J. Viral Hepat. 21, 357–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Dohmen, K. et al. The incidence and risk factors for the development of hepatocellular carcinoma after peginterferon plus ribavirin therapy for chronic hepatitis C. Hepatogastroenterology 60, 2034–2038 (2013).

    CAS  PubMed  Google Scholar 

  110. 110

    Van der Meer, A. J. et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308, 2584–2593 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Morgan, R. L. et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann. Intern. Med. 158, 329–337 (2013).

    Article  PubMed  Google Scholar 

  112. 112

    Foster, G. R. et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N. Engl. J. Med. 373, 2608–2617 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Singal, A. G. & El-Serag, H. B. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin. Gastroenterol. Hepatol. 13, 2140–2151 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Younossi, Z. M. et al. The impact of hepatitis C burden: an evidence-based approach. Aliment. Pharmacol. Ther. 39, 518–531 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Bosch, J. & Forns, X. Therapy. Statins and liver disease: from concern to ‘wonder’ drugs? Nat. Rev. Gastroenterol. Hepatol. 12, 320–321 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Zhang, H., Gao, C., Fang, L., Zhao, H.-C. & Yao, S.-K. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis. Scand. J. Gastroenterol. 48, 78–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Zhang, X. et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology 60, 2008–2016 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Zhang, B.-H., Yang, B.-H. & Tang, Z.-Y. Randomized controlled trial of screening for hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 130, 417–422 (2004).

    PubMed  Google Scholar 

  119. 119

    Yeh, Y.-P. et al. Evaluation of abdominal ultrasonography mass screening for hepatocellular carcinoma in Taiwan. Hepatology 59, 1840–1849 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Tong, M. J., Sun, H.-E., Hsien, C. & Lu, D. S. K. Surveillance for hepatocellular carcinoma improves survival in Asian–American patients with hepatitis B: results from a community-based clinic. Dig. Dis. Sci. 55, 826–835 (2010).

    Article  PubMed  Google Scholar 

  121. 121

    Tanaka, H. et al. Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. Liver Int. 26, 543–551 (2006).

    Article  PubMed  Google Scholar 

  122. 122

    Wong, G. L.-H. et al. Surveillance programme for hepatocellular carcinoma improves the survival of patients with chronic viral hepatitis. Liver Int. 28, 79–87 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Taura, N. et al. Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study. Oncol. Rep. 14, 999–1003 (2005).

    PubMed  Google Scholar 

  124. 124

    Chan, A. C. Y. et al. Changing paradigm in the management of hepatocellular carcinoma improves the survival benefit of early detection by screening. Ann. Surg. 247, 666–673 (2008).

    Article  PubMed  Google Scholar 

  125. 125

    Nouso, K. et al. Cost-effectiveness of the surveillance program of hepatocellular carcinoma depends on the medical circumstances. J. Gastroenterol. Hepatol. 23, 437–444 (2008).

    Article  PubMed  Google Scholar 

  126. 126

    Lin, O. S., Keeffe, E. B., Sanders, G. D. & Owens, D. K. Cost-effectiveness of screening for hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. Aliment. Pharmacol. Ther. 19, 1159–1172 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    Arguedas, M. R., Chen, V. K., Eloubeidi, M. A. & Fallon, M. B. Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis. Am. J. Gastroenterol. 98, 679–690 (2003).

    Article  PubMed  Google Scholar 

  128. 128

    Andersson, K. L., Salomon, J. A., Goldie, S. J. & Chung, R. T. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 6, 1418–1424 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Cucchetti, A. et al. Cost-effectiveness of semi-annual surveillance for hepatocellular carcinoma in cirrhotic patients of the Italian liver cancer population. J. Hepatol. 56, 1089–1096 (2012).

    Article  PubMed  Google Scholar 

  130. 130

    Sarasin, F. P., Giostra, E. & Hadengue, A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child–Pugh class A cirrhosis. Am. J. Med. 101, 422–434 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Thompson Coon, J. et al. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol. Assess. 11, 1–206 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    Saab, S. et al. Hepatocellular carcinoma screening in patients waiting for liver transplantation: a decision analytic model. Liver Transpl. 9, 672–681 (2003).

    Article  PubMed  Google Scholar 

  133. 133

    Naugler, W. E. & Sonnenberg, A. Survival and cost-effectiveness analysis of competing strategies in the management of small hepatocellular carcinoma. Liver Transpl. 16, 1186–1194 (2010).

    Article  PubMed  Google Scholar 

  134. 134

    Thompson Coon, J. et al. Surveillance of cirrhosis for hepatocellular carcinoma: a cost-utility analysis. Br. J. Cancer 98, 1166–1175 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Patel, D., Terrault, N. A., Yao, F. Y., Bass, N. M. & Ladabaum, U. Cost-effectiveness of hepatocellular carcinoma surveillance in patients with hepatitis C virus-related cirrhosis. Clin. Gastroenterol. Hepatol. 3, 75–84 (2005).

    Article  PubMed  Google Scholar 

  136. 136

    Kang, J. Y., Lee, T. P., Yap, I. & Lun, K. C. Analysis of cost-effectiveness of different strategies for hepatocellular carcinoma screening in hepatitis B virus carriers. J. Gastroenterol. Hepatol. 7, 463–468 (1992).

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Shih, S. T.-F., Crowley, S. & Sheu, J.-C. Cost-effectiveness analysis of a two-stage screening intervention for hepatocellular carcinoma in Taiwan. J. Formos. Med. Assoc. 109, 39–55 (2010).

    Article  PubMed  Google Scholar 

  138. 138

    Marrero, J. A. et al. α-Fetoprotein, des-γ carboxyprothrombin, and lectin-bound α-fetoprotein in early hepatocellular carcinoma. Gastroenterology 137, 110–118 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Asaoka, Y. et al. Frequency of and predictive factors for vascular invasion after radiofrequency ablation for hepatocellular carcinoma. PLoS ONE 9, e111662 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Kudo, A. et al. Does the preoperative α-fetoprotein predict the recurrence and mortality after hepatectomy for hepatocellular carcinoma without macrovascular invasion in patients with normal liver function? Hepatol. Res. 44, E437–E446 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    Shirabe, K. et al. New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma. Liver Int. 34, 937–941 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Park, H. et al. Clinical usefulness of double biomarkers AFP and PIVKA-II for subdividing prognostic groups in locally advanced hepatocellular carcinoma. Liver Int. 34, 313–321 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Nakazawa, T. et al. Early increase in α-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Eur. J. Gastroenterol. Hepatol. 25, 683–689 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Park, W.-H. et al. Clinical utility of des-γ-carboxyprothrombin kinetics as a complement to radiologic response in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. J. Vasc. Interv. Radiol. 23, 927–936 (2012).

    Article  PubMed  Google Scholar 

  145. 145

    Han, K.-H. et al. Survival of hepatocellular carcinoma patients may be improved in surveillance interval not more than 6 months compared with more than 6 months: a 15-year prospective study. J. Clin. Gastroenterol. 47, 538–544 (2013).

    Article  PubMed  Google Scholar 

  146. 146

    Trinchet, J.-C. et al. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology 54, 1987–1997 (2011).

    Article  PubMed  Google Scholar 

  147. 147

    Santi, V. et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J. Hepatol. 53, 291–297 (2010).

    Article  PubMed  Google Scholar 

  148. 148

    Wang, J.-H. et al. Hepatocellular carcinoma surveillance at 4- versus 12-month intervals for patients with chronic viral hepatitis: a randomized study in community. Am. J. Gastroenterol. 108, 416–424 (2013).

    Article  PubMed  Google Scholar 

  149. 149

    Mitchell, D. G., Bruix, J., Sherman, M. & Sirlin, C. B. LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. Hepatology 61, 1056–1065 (2015).

    Article  PubMed  Google Scholar 

  150. 150

    Khalili, K. et al. Optimization of imaging diagnosis of 1–2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J. Hepatol. 54, 723–728 (2011).

    Article  PubMed  Google Scholar 

  151. 151

    Sangiovanni, A. et al. The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 59, 638–644 (2010).

    Article  PubMed  Google Scholar 

  152. 152

    Lencioni, R., Cioni, D., Della Pina, C., Crocetti, L. & Bartolozzi, C. Imaging diagnosis. Semin. Liver Dis. 25, 162–170 (2005).

    Article  PubMed  Google Scholar 

  153. 153

    Silva, M. A. et al. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut 57, 1592–1596 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    The International Consensus Group of Hepatocellular Neoplasia. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49, 658–664 (2009).

    Article  Google Scholar 

  155. 155

    Libbrecht, L. et al. Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am. J. Surg. Pathol. 30, 1405–1411 (2006).

    Article  PubMed  Google Scholar 

  156. 156

    Tremosini, S. et al. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut 61, 1481–1487 (2012).

    Article  PubMed  Google Scholar 

  157. 157

    Di Tommaso, L. et al. Diagnostic accuracy of clathrin heavy chain staining in a marker panel for the diagnosis of small hepatocellular carcinoma. Hepatology 53, 1549–1557 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Llovet, J. M., Brú, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999). A seminal study proposing the BCLC staging system, now accepted by European and American guidelines of management of HCC.

    Article  CAS  PubMed  Google Scholar 

  159. 159

    Bruix, J., Han, K., Gores, G., Llovet, J. M. & Mazzaferro, V. Liver cancer: approaching a personalized care. J. Hepatol. 62, S144–156 (2015).

    Article  Google Scholar 

  160. 160

    Yau, T. et al. Development of Hong Kong liver cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 146, 1691–1700.e3 (2014).

    Article  PubMed  Google Scholar 

  161. 161

    The Cancer of the Liver Italian Program (CLIP) Investigators A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 28, 751–755 (1998).

  162. 162

    Sobin, L. H. & Compton, C. C. TNM seventh edition: what's new, what's changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer 116, 5336–5339 (2010).

    Article  PubMed  Google Scholar 

  163. 163

    Kudo, M., Chung, H. & Osaki, Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging score (JIS score). J. Gastroenterol. 38, 207–215 (2003).

    Article  PubMed  Google Scholar 

  164. 164

    Bruix, J. et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 111, 1018–1022 (1996).

    Article  CAS  PubMed  Google Scholar 

  165. 165

    Llovet, J. M., Schwartz, M. & Mazzaferro, V. Resection and liver transplantation for hepatocellular carcinoma. Semin. Liver Dis. 25, 181–200 (2005).

    Article  PubMed  Google Scholar 

  166. 166

    Llovet, J. M., Fuster, J. & Bruix, J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30, 1434–1440 (1999).

    Article  CAS  PubMed  Google Scholar 

  167. 167

    Imamura, H. et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J. Hepatol. 38, 200–207 (2003).

    Article  PubMed  Google Scholar 

  168. 168

    Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a Phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. 169

    Takayama, T. et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356, 802–807 (2000).

    Article  CAS  PubMed  Google Scholar 

  170. 170

    Muto, Y. et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N. Engl. J. Med. 334, 1561–1567 (1996).

    Article  CAS  PubMed  Google Scholar 

  171. 171

    Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334, 693–699 (1996). This paper defines the Milan criteria for selecting candidates for liver transplantation; these criteria are currently adopted by most transplant units globally.

    Article  CAS  PubMed  Google Scholar 

  172. 172

    Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 10, 35–43 (2009).

    Article  PubMed  Google Scholar 

  173. 173

    Toso, C. et al. Total tumor volume and α-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: a prospective validation. Hepatology 62, 158–165 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. 174

    Miltiadous, O. et al. Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. J. Hepatol. 63, 1368–1377 (2015).

    Article  PubMed  Google Scholar 

  175. 175

    Livraghi, T. et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 47, 82–89 (2008).

    Article  PubMed  Google Scholar 

  176. 176

    Lo, C.-M. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35, 1164–1171 (2002). This RCT demonstrates the efficacy of TACE in patients with intermediate-stage HCC.

    Article  CAS  PubMed  Google Scholar 

  177. 177

    Kudo, M. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized Phase III trial. Hepatology 60, 1697–1707 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. 178

    Burrel, M. et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using drug eluting beads. Implications for clinical practice and trial design. J. Hepatol. 56, 1330–1335 (2012).

    Article  PubMed  Google Scholar 

  179. 179

    Salem, R. et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 140, 497–507.e2 (2011).

    Article  PubMed  Google Scholar 

  180. 180

    Cheng, A.-L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a Phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    Yeo, W. et al. A randomized Phase III study of doxorubicin versus cisplatin/interferon α-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J. Natl Cancer Inst. 97, 1532–1538 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. 182

    D'Amico, G., Garcia-Tsao, G. & Pagliaro, L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J. Hepatol. 44, 217–231 (2006).

    Article  PubMed  Google Scholar 

  183. 183

    Eguchi, S. et al. Comparison of the outcomes between an anatomical subsegmentectomy and a non-anatomical minor hepatectomy for single hepatocellular carcinomas based on a Japanese nationwide survey. Surgery 143, 469–475 (2008).

    Article  PubMed  Google Scholar 

  184. 184

    Palavecino, M. et al. Major hepatic resection for hepatocellular carcinoma with or without portal vein embolization: perioperative outcome and survival. Surgery 145, 399–405 (2009).

    Article  PubMed  Google Scholar 

  185. 185

    Vouche, M. et al. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J. Hepatol. 59, 1029–1036 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  186. 186

    Cherqui, D. Laparoscopic liver resection: a new paradigm in the management of hepatocellular carcinoma? J. Hepatol. 63, 540–542 (2015).

    Article  PubMed  Google Scholar 

  187. 187

    Ishizawa, T. et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134, 1908–1916 (2008).

    Article  PubMed  Google Scholar 

  188. 188

    Franssen, B. et al. Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular carcinoma: a retrospective analysis of a single North American center. Ann. Surg. 260, 650–656 (2014).

    Article  PubMed  Google Scholar 

  189. 189

    Roayaie, S., Bassi, D., Tarchi, P., Labow, D. & Schwartz, M. Second hepatic resection for recurrent hepatocellular cancer: a western experience. J. Hepatol. 55, 346–350 (2011).

    Article  PubMed  Google Scholar 

  190. 190

    Fuks, D. et al. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology 55, 132–140 (2012).

    Article  PubMed  Google Scholar 

  191. 191

    Lau, W. Y. et al. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 353, 797–801 (1999).

    Article  CAS  PubMed  Google Scholar 

  192. 192

    Clavien, P.-A. et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 13, e11–e22 (2012). This publication outlines consensus guidelines for the management of HCC with liver transplantation.

    Article  PubMed  Google Scholar 

  193. 193

    Lesurtel, M., Mü llhaupt, B., Pestalozzi, B. C., Pfammatter, T. & Clavien, P.-A. Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: an evidence-based analysis. Am. J. Transplant. 6, 2644–2650 (2006).

    Article  CAS  PubMed  Google Scholar 

  194. 194

    Kulik, L. M. et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am. J. Transplant. 12, 2997–3007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Toso, C., Merani, S., Bigam, D. L., Shapiro, A. M. J. & Kneteman, N. M. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 51, 1237–1243 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. 196

    Schnitzbauer, A. A. et al. A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 10, 190 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label Phase 3 trial. Transplantation 100, 116–125 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  198. 198

    Vitale, A. et al. Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study. Lancet Oncol. 12, 654–662 (2011).

    Article  PubMed  Google Scholar 

  199. 199

    Menon, K. V., Hakeem, A. R. & Heaton, N. D. Review article: liver transplantation for hepatocellular carcinoma — a critical appraisal of the current worldwide listing criteria. Aliment. Pharmacol. Ther. 40, 893–902 (2014).

    Article  CAS  PubMed  Google Scholar 

  200. 200

    Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33, 1394–1403 (2001).

    Article  CAS  PubMed  Google Scholar 

  201. 201

    Yao, F. Y. et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 48, 819–827 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  202. 202

    Kowdley, K. V. et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N. Engl. J. Med. 370, 1879–1888 (2014).

    Article  CAS  PubMed  Google Scholar 

  203. 203

    Ahmed, M. et al. Image-guided tumor ablation: standardization of terminology and reporting criteria — a 10-year update. Radiology 273, 241–260 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  204. 204

    Lencioni, R. & Crocetti, L. Image-guided ablation for hepatocellular carcinoma. Recent Results Cancer Res. 190, 181–194 (2013).

    Article  PubMed  Google Scholar 

  205. 205

    Cho, Y. K. et al. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 49, 453–459 (2009).

    Article  PubMed  Google Scholar 

  206. 206

    Orlando, A., Leandro, G., Olivo, M., Andriulli, A. & Cottone, M. Radiofrequency thermal ablation versus percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am. J. Gastroenterol. 104, 514–524 (2009).

    Article  PubMed  Google Scholar 

  207. 207

    Shiina, S. et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am. J. Gastroenterol. 107, 569–577 (2012).

    Article  CAS  PubMed  Google Scholar 

  208. 208

    Salem, R. et al. Research reporting standards for radioembolization of hepatic malignancies. J. Vasc. Interv. Radiol. 22, 265–278 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  209. 209

    Bruix, J., Sala, M. & Llovet, J. M. Chemoembolization for hepatocellular carcinoma. Gastroenterology 127, S179–S188 (2004).

    Article  CAS  PubMed  Google Scholar 

  210. 210

    Raoul, J.-L. et al. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat. Rev. 37, 212–220 (2011).

    Article  PubMed  Google Scholar 

  211. 211

    Golfieri, R. et al. Randomised controlled trial of doxorubicin-eluting beads versus conventional chemoembolisation for hepatocellular carcinoma. Br. J. Cancer 111, 255–264 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. 212

    Sangro, B. & Salem, R. Transarterial chemoembolization and radioembolization. Semin. Liver Dis. 34, 435–443 (2014).

    Article  PubMed  Google Scholar 

  213. 213

    Lencioni, R. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J. Hepatol.http://dx.doi.org/10.1016/j.jhep.2016.01.012 (2016).

  214. 214

    Oliveri, R. S., Wetterslev, J. & Gluud, C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst. Rev. 3, CD004787 (2011).

    Google Scholar 

  215. 215

    Sangro, B., Iñarrairaegui, M. & Bilbao, J. I. Radioembolization for hepatocellular carcinoma. J. Hepatol. 56, 464–473 (2012).

    Article  PubMed  Google Scholar 

  216. 216

    Sangro, B. et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 54, 868–878 (2011).

    Article  PubMed  Google Scholar 

  217. 217

    Meyer, T. et al. A randomised Phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation versus embolisation alone for hepatocellular carcinoma. Br. J. Cancer 108, 1252–1259 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. 218

    Llovet, J. M., Villanueva, A., Lachenmayer, A. & Finn, R. S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol. 12, 408–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  219. 219

    Qin, S. et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J. Clin. Oncol. 31, 3501–3508 (2013).

    Article  CAS  PubMed  Google Scholar 

  220. 220

    Bruix, J. et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a Phase III trial. J. Hepatol. 57, 821–829 (2012).

    Article  CAS  PubMed  Google Scholar 

  221. 221

    Llovet, J. M. et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 18, 2290–2300 (2012).

    Article  CAS  PubMed  Google Scholar 

  222. 222

    Wilhelm, S. M. et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7, 3129–3140 (2008).

    Article  CAS  PubMed  Google Scholar 

  223. 223

    Llovet, J. M. et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl Cancer Inst. 100, 698–711 (2008). This paper describes consensus guidelines for the design of clinical trials in HCC.

    Article  PubMed  Google Scholar 

  224. 224

    Johnson, P. J. et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized Phase III BRISK-FL study. J. Clin. Oncol. 31, 3517–3524 (2013).

    Article  CAS  PubMed  Google Scholar 

  225. 225

    Cheng, A.-L. et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized Phase III trial. J. Clin. Oncol. 31, 4067–4075 (2013).

    Article  CAS  PubMed  Google Scholar 

  226. 226

    Cainap, C. et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized Phase III trial. J. Clin. Oncol. 33, 172–179 (2015).

    Article  CAS  PubMed  Google Scholar 

  227. 227

    Zhu, A. X. et al. SEARCH: a Phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 33, 559–566 (2015).

    Article  CAS  PubMed  Google Scholar 

  228. 228

    Llovet, J. M. et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized Phase III BRISK-PS study. J. Clin. Oncol. 31, 3509–3516 (2013).

    Article  CAS  PubMed  Google Scholar 

  229. 229

    Zhu, A. X. et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 312, 57–67 (2014).

    Article  CAS  PubMed  Google Scholar 

  230. 230

    Zhu, A. X. et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, Phase 3 trial. Lancet Oncol. 20, 859–870 (2015).

    Article  CAS  Google Scholar 

  231. 231

    Llovet, J. M. & Hernandez-Gea, V. Hepatocellular carcinoma: reasons for Phase III failure and novel perspectives on trial design. Clin. Cancer Res. 20, 2072–2079 (2014).

    Article  CAS  PubMed  Google Scholar 

  232. 232

    Lencioni, R. & Llovet, J. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).

    Article  CAS  PubMed  Google Scholar 

  233. 233

    Coulouarn, C., Factor, V. M. & Thorgeirsson, S. S. Transforming growth factor-β gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 47, 2059–2067 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    Faivre, S. J., Santoro, A. & Kelley, R. K. A Phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. Abstr. 32, LBA173 (2014).

    Article  Google Scholar 

  235. 235

    Finn, R. S. Gains in FGF19 are predictive of response to the fibroblast growth factor receptor (FGFR) small molecule tyrosine kinase inhibitor BGJ 398 in vitro. Cancer Res. Abstr. 72, 3858 (2012).

    Article  Google Scholar 

  236. 236

    Hagel, M. et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 5, 424–437 (2015).

    Article  CAS  PubMed  Google Scholar 

  237. 237

    Calvisi, D. F. et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130, 1117–1128 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. 238

    O'Neil, B. H. et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 29, 2350–2356 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. 239

    Lim, H. Y. et al. A Phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86–9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin. Cancer Res. 20, 5976–5985 (2014).

    Article  CAS  PubMed  Google Scholar 

  240. 240

    Goyal, L., Muzumdar, M. D. & Zhu, A. X. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin. Cancer Res. 19, 2310–2318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. 241

    Xiang, Q. et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin. Cancer Res. 20, 2959–2970 (2014).

    Article  CAS  PubMed  Google Scholar 

  242. 242

    Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2014).

    Article  CAS  PubMed  Google Scholar 

  243. 243

    Butterfield, L. H. et al. A Phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four α-fetoprotein peptides. Clin. Cancer Res. 12, 2817–2825 (2006).

    Article  CAS  PubMed  Google Scholar 

  244. 244

    Palmer, D. H. et al. A Phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49, 124–132 (2009).

    Article  PubMed  Google Scholar 

  245. 245

    Sangro, B. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 59, 81–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  246. 246

    El-Khoueiry, A. et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J. Clin Oncol. Abstr. 33, LBA101 (2015).

    Article  Google Scholar 

  247. 247

    Yeo, W. et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter Phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J. Clin. Oncol. 30, 3361–3367 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. 248

    Bitzer, M. et al. Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study. J. Clin Oncol. Abstr. 30, 4115 (2012).

    Google Scholar 

  249. 249

    US National Library of Science. A study of RO5137382 (GC33) in patients with advanced or metastatic hepatocellular carcinoma. ClinicalTrials.gov[online], (2015).

  250. 250

    Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. 251

    Van Allen, E. M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2014).

    Article  CAS  Google Scholar 

  252. 252

    Tovar, V. et al. Tumor initiating cells and IGF/FGF signaling contribute to sorafenib resistance in hepatocellular carcinoma. Guthttp://dx.doi.org/10.1136/gutjnl-2015-309501 (2015).

  253. 253

    Chie, W.-C. et al. International cross-cultural field validation of an European Organization for Research and Treatment of Cancer questionnaire module for patients with primary liver cancer, the European Organization for Research and Treatment of Cancer quality-of-life ques. Hepatology 55, 1122–1129 (2012).

    Article  PubMed  Google Scholar 

  254. 254

    Blazeby, J. M. et al. Development of a questionnaire module to supplement the EORTC QLQ-C30 to assess quality of life in patients with hepatocellular carcinoma, the EORTC QLQ-HCC18. Eur. J. Cancer 40, 2439–2444 (2004).

    Article  PubMed  Google Scholar 

  255. 255

    Huang, G. et al. Quality of life after surgical resection compared with radiofrequency ablation for small hepatocellular carcinomas. Br. J. Surg. 101, 1006–1015 (2014).

    Article  CAS  PubMed  Google Scholar 

  256. 256

    Salem, R. et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin. Gastroenterol. Hepatol. 11, 1358–1365.e1 (2013).

    Article  PubMed  Google Scholar 

  257. 257

    Afdhal, N. et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N. Engl. J. Med. 370, 1889–1898 (2014).

    Article  CAS  PubMed  Google Scholar 

  258. 258

    Kahn, M. Can we safely target the WNT pathway? Nat. Rev. Drug Discov. 13, 513–532 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. 259

    Roayaie, S. et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62, 440–451 (2015).

    Article  CAS  PubMed  Google Scholar 

  260. 260

    Park, J.-W. et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 35, 2155–2166 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  261. 261

    Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. 262

    Weinstein, I. B. Cancer. Addiction to oncogenes — the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  263. 263

    Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. 264

    Nault, J.-C. & Villanueva, A. Intratumor molecular and phenotypic diversity in hepatocellular carcinoma. Clin. Cancer Res. 21, 1786–1788 (2015).

    Article  CAS  PubMed  Google Scholar 

  265. 265

    McGranahan, N. & Swanton, C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27, 15–26 (2015).

    Article  CAS  PubMed  Google Scholar 

  266. 266

    Gridelli, C. et al. Non-small-cell lung cancer. Nat. Rev. Dis. Primers 1, 1–16 (2015).

    Article  Google Scholar 

  267. 267

    Tabernero, J. et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 16, 937–948 (2015).

    Article  CAS  PubMed  Google Scholar 

  268. 268

    Crowley, E., Di Nicolantonio, F., Loupakis, F. & Bardelli, A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10, 472–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  269. 269

    Thierry, A. R. et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat. Med. 20, 430–435 (2014).

    Article  CAS  PubMed  Google Scholar 

  270. 270

    Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.M.L. has grants from the US National Cancer Institute (NCI) (P30CA165979), the European Commission Horizon 2020 (HEP-CAR, proposal number 667273–2), the Samuel Waxman Cancer Research Foundation, the Grant I+D Program (SAF2013-41027) and the Asociación Española Contra el Cáncer (AECC). J.Z.-R. has received funding from INSERM, the French National Cancer Institute (INCa) and The Ligue Contre le Cancer (équipe Labellisée). E.P. receives funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the European Research Council and the Israel Science Foundation. The authors thank R. Montal, S. Torrecilla, A. Farré and M. Boteller (Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS — Hospital Clinic, Barcelona, Spain) for their support in editing references, figures and tables for this manuscript.

Author information

Affiliations

Authors

Contributions

Introduction (J.M.L.); Epidemiology (G.G.); Mechanisms/pathophysiology (J.Z.-R. and E.P.); Diagnosis, screening and prevention (M.Sh. and G.G.); Management (M.Sc., B.S. and J.M.L.); Quality of life (M.Sh.); Outlook (J.M.L., G.G. and E.P.); overview of Primer (J.M.L.).

Corresponding author

Correspondence to Josep M. Llovet.

Ethics declarations

Competing interests

J.M.L. receives research support and grants from Bayer Pharmaceuticals, Blueprint Medicines, Bristol-Myers Squibb and Boehringer Ingelheim, and is a consultant for Bayer Pharmaceuticals, Bristol-Myers Squibb, Blueprint Medicines, Eli Lilly and Company, Celsion, Biocompatibles, Boehringer Ingelheim, Novartis and GlaxoSmithKline. M.Sh. is a consultant for Bayer Pharmaceuticals, Celsion, ArQule, H3 Biomedicine and Merck. J.Z.-R. is a consultant for IntegraGen. B.S. has received lecturing and consulting fees from Bayer Healthcare and Sirtex Medical. G.G. is in the Data Safety and Monitoring committee for a Bayer Pharmaceuticals trial in hepatocellular carcinoma. M.Sc. and E.P. have nothing to disclose.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Llovet, J., Zucman-Rossi, J., Pikarsky, E. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2, 16018 (2016). https://doi.org/10.1038/nrdp.2016.18

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing